Coronary artery disease (xe2x80x9cCADxe2x80x9d) is a leading cause of death worldwide. More than 6 million Americans have CAD, of which some 1.5 million suffer heart attacks (myocardial infarction), resulting in 500,000 deaths and nearly 1 million hospitalizations annually in the U.S. CAD is characterized by narrowing of the arteries that feed the heart muscle (xe2x80x9cmyocardiumxe2x80x9d); without adequate blood supply, the tissue becomes starved for oxygen (xe2x80x9cischemicxe2x80x9d), and the heart does not pump as efficiently. A heart attack (which usually indicates a complete blockage of a coronary artery) can result in a portion of the heart muscle being ischemic for a prolonged time and then dying, which can permanently reduce the patient""s ability to perform exercise, such as walking. The treatment of CAD includes preventive measures (modification of diet and/or exercise, reduction in hypercholesterolemia through various drugs, etc.), minimally invasive clearing of arteries (angioplasty, atherectomy, intravascular stenting), and surgical bypass of the diseased artery(ies) (coronary artery bypass surgery, xe2x80x9cCABGxe2x80x9d). While preventive measures have helped to reduce the number of CAD patients, CAD remains one of the greatest health problems in the world today.
Angioplasty and related catheter-based procedures can unblock some arteries, but the blockages, or xe2x80x9cstenosesxe2x80x9d, typically return, a condition known as xe2x80x9crestenosis,xe2x80x9d within 6-18 months due to intimal hyperplasia, which is creation of scar tissue from the traumatic vessel wall damage during the angioplasty procedure. The use of stents (metal or polymer tubes or coils which hold the artery open) has decreased the restenosis rate by about one half. Radioactive devices (catheters and stents) are being developed to further reduce the restenosis rate. However, angioplasty has fundamental limitations, which are unlikely to ever be solved completely. These include inability to reach smaller vessels, morbidity associated with failed angioplasty procedures, poor success rate in certain vessels, e.g., saphenous vein grafts, and general inability to completely revascularize the heart muscle (myocardium). Approximately 800,000 coronary angioplasty procedures are performed annually in the U.S.
Coronary artery bypass procedures are performed on approximately 400,000 people in the U.S. annually, and nearly 800,000 people worldwide.
Although the primary result of CABG is generally satisfactory, the saphenous veins used in most patients become blocked 10-15 years after surgery. Also, CABG procedures are very traumatic, and carry a risk of mortality around 1-3%. Although xe2x80x9cheart portxe2x80x9d, xe2x80x9coff-pumpxe2x80x9d, and other minimally invasive types of CABG procedures are being developed, they are all quite invasive and/or utilize a pump and oxygenator (xe2x80x9cheart-lung machinexe2x80x9d), which introduces additional trauma to the patient.
Transmyocardial revascularization (TMR) using a laser (sometimes referred to as TMLR, LTMR, PMR, PTMR, or DMR) has been developed over the past decade, initially by a company called PLC Systems, Inc., of Franklin, Mass. PLC""s system utilizes a high power (800-1000 W) carbon dioxide (CO2) laser which drills small channels in the outside (epicardial) surface of the myocardium in a surgical procedure. The holes communicate with the left ventricle, which delivers blood directly to the heart muscle, mimicking the reptilian heart. Many other companies are developing laser TMR systems, most introducing the laser light via optical fibers through a flexible catheter, making the procedure less-invasive. These companies include Eclipse Surgical Technologies, Inc., of Sunnyvale, Calif., and Helionetics, Inc., of Van Nuys, Calif. The Eclipse TMR system uses a Ho:YAG laser with a catheter-delivered fiber optic probe for contact delivery to the myocardium. The Helionetics system is based on an excimer laser. In addition to the holmium:YAG and excimer lasers, and other types of lasers have been proposed for TMR.
While the channels created during TMR are known to close within 2-4 weeks, most patients tend to improve clinically over a period of 2-6 months.
Such clinical improvement may be demonstrated by reduction in chest pain (xe2x80x9canginaxe2x80x9d), and a dramatic increase in exercise tolerance (xe2x80x9cETTxe2x80x9d, or treadmill test). The mechanism of laser TMR is not fully understood, but it is postulated that the laser causes near-term relief of angina through denervation or patent channels, with subsequent long-term clinical improvement due to angiogenesis, i.e., growth of new blood vessels, mainly capillaries, which perfuse the heart muscle. These new xe2x80x9ccollateralxe2x80x9d vessels enable blood to reach downstream (xe2x80x9cdistalxe2x80x9d) ischemic tissues, despite blockages in the coronary arteries. Some of the possible mechanisms by which the laser induces angiogenesis could include activation of growth factors by light, thermal, mechanical, cavitational or shockwave means. In fact, all lasers which have been successfully used for TMR are pulsed systems, and are known to create shock waves in tissue, and resulting cavitation effects.
Cavitation can be induced in a liquid-rich environment like tissue. An opening or cavity can be created in a fluid by thermal vaporization or an rapid movement of a solid through the liquid (such as explosive expansion of a gas bubble formed in the tissue). When energy is focused into a small area of a liquid in a short time, e.g.,  less than 1 ms, the temperature can rapidly rise above boiling temperature and vapor is formed. Typically, the vapor volume is over 1000 times the original liquid volume. The vapor is formed at very high pressure and an explosive vapor bubble will be created, rapidly expanding to equalize the internal bubble pressure to ambient pressures. This bubble creates an opening in the liquid (or tissue) environment. While the bubble is expanding, the temperature inside will decrease and drop below the boiling point. The vapor then turn backs into liquid. Due to the momentum of expansion however, the bubble expands, further creating a semi-vacuum. At some point, the negative pressure overcomes the momentum of expansion, and the process becomes an implosion. Like the expansion, the implosion can be very fast, inducing a high momentum in the surrounding liquid. The motion of the liquid during implosion will be spherically symmetric, concentrated in the middle of the imploding bubble. The collision at the moment of total implosion is very forceful and is capable of creating supersonic density waves in the liquid, or xe2x80x9cshock-waves.xe2x80x9d If the energy release at the start of bubble formation is also very concentrated, a shock-wave can also be generated at the very start of the bubble.
Cavitation bubbles can also be formed by focusing shock waves into the liquid/tissue from an external shock wave generator. Shock-wave generators create locally very high temperatures inducing plasmas in liquids. The heat transfer to the environment subsequently creates a vapor bubble inducing the process as described above.
Another method to induce cavitation effects in liquid is by displacing the liquid at high speed by moving a solid object through the liquid. Because a delay occurs before the liquid can fill in the gap behind the object moving through the liquid, a vacuum will briefly form. The liquid filling this vacuum will be accelerated to very high speeds. At the instant the gap is filled, the liquid collides within the center of the gap, forming a shock-wave. In tissue environment, cells are sucked from their matrix by the rapidly moving liquid causing the tissue itself to effectively become liquefied.
Catheters have been previously developed which can deliver high intensity ultrasound energy to the coronary arteries for the purpose of removing thrombus (blood clots) and/or atherosclerotic plaque (see, e.g., U.S. Pat. No. 5,524,620 of Rosenschein) [note that these catheters are quite different from the intravascular imaging devices that use low intensity ultrasonic signals to probe and image arterial cross-sections]. These catheters could be modified to deliver ultrasound energy to the myocardium.
Catheters have also been previously developed which can remove tissue via spark erosion, electrical discharge, or other shock wave producing technologies. These shock waves, if of sufficient amplitude in a localized region, can create a cavitation effect. This is the principle behind shock-wave lithotripters, which are used to non-invasively break-up kidney and ureteral stones (xe2x80x9ccalculixe2x80x9d). Such systems are known in the art (particularly in the fields of urology and gastroenterology), but can produce severe tissue damagexe2x80x94typically much greater than the damage produced by laser TMR.
Initially, TMR was performed on patients who were not acceptable candidates for angioplasty or bypass surgery. It is hoped that TMR could be a replacement for bypass surgery, for those patients who""s arteries continue to restenose after angioplasty. Ultimately, with a non-invasive TMR approach as described herein, TMR could be used on CAD patients instead of (or prior to) angioplasty, CABG or any other revascularization procedure. In addition to the possibility of the TMR procedure replacing conventional revascularization procedures, it is currently being used as an adjunct to CABG surgery; in this case, areas of the myocardium where blood flow cannot be completely restored using surgical bypass (e.g., because the vessels are too small or too clogged) can be treated with TMR, enhancing the blood flow to these distal regions, and improving the overall outcome of the CABG procedure.
In parallel with laser TMR developments have been developments of angiogenic growth factors, which can also stimulate small capillary growth (xe2x80x9cangiogenesisxe2x80x9d) in heart muscle. Vascular endothelial growth factor (xe2x80x9cVEGFxe2x80x9d), angiopoetin-1 and -2, basic fibroblast growth factor (bFGF), and other growth factors are now being studied, with therapeutic angiogenesis being demonstrated in animal models. A few studies have progressed to testing on humans. Although it is too early to make a definitive conclusion, it appears that angiogenesis created by these growth factors may help CAD patients clinically. However, the administration of these drugs, once they are approved by the FDA, will either be systemicxe2x80x94opening the potential for unwanted vessel growth, for example in the eye or in tumors; or they may require direct introduction of the growth factor(s) into the myocardium. Therefore, companies are developing devices for injecting growth factors into heart muscle, including lasers, catheter-based systems, and other devices.
Current technologies for revascularizing the heartxe2x80x94including all commercialized TMR approaches to-datexe2x80x94have severe limitations. Laser TMR systems are very expensive ($250,000-500,000). The original (PLC) system requires open chest surgery, which is nearly as traumatic as CABG surgery. Some catheter-based TMR systems have recently been approved by the FDA, but they are also expensive ($250,000 or more for the laser, and $1000 or more for the catheter). Catheter-based systems may also require a guidance technique, such as electrical mapping, which introduces further costs.
The development of growth factors, and the delivery of genes or proteins which introduce or activate specific growth factors is ongoing. Many growth factors are combined with a recombinant adenovirus to provide an efficient gene delivery vector for a variety of cell types and tissues. However, the long-term complications of the use of these adenoviral vectors, e.g., cancerous growths, and systemic effects, e.g., viral infection, are currently unknown. If direct targeting to the myocardium is required, catheter-based systems may be necessary. Some of these catheter systems even utilize an expensive laser to make channels or pockets, where the drug is injected.
While the mechanism of action of TMR is not fully understood, it must rely on one of several possible effects of pulsed lasers: light, heat, and/or shock waves (and resulting cavitation). Neither light nor heat has previously shown any ability to improve the condition of CAD patients, although various surgical instruments using heat have been used for decades in heart surgery. Therefore, the most likely characteristic of laser energy which could cause angiogenesis is the cavitation resulting from shock waves produced by explosive vaporization of tissue using high power pulsed laser systems.
As cavitation phenomena appear to be the likely source of trauma which stimulates expression of natural growth factors responsible for myocardial angiogenesis, a rational and cost-effective approach to TMR would be to select an appropriate shock wave generator, and a delivery system that can utilize these shock waves to create cavitation in the myocardium. The laser may not be the best candidate for this function. Lasers produce both shock waves and heat, and heat has often been found to be xe2x80x98badxe2x80x99 for the heart (e.g., thermal angioplasty). Lasers also usually represent the most expensive technology that can provide a given physical result, and current TMR systems are not cost-effective (hospitals are currently paying $500,000 for a laser to generate shock waves that could also be obtained using a $50,000 electromechanical generator system).
Studies using focused ultrasound for TMR were first reported by Smith and Hynynen in 1998. (Ultrasound in Medicine and Biology, Vol. 24, No. 7, 1998, pp. 1045-1054.) Ultrasonic transducers were used to deliver focused ultrasound energy to animal myocardium. The authors speculate that, potentially, a phased array of transducers could be used to focus shock waves into human hearts (around or between the ribs) completely non-invasively. Mechanisms of achieving the desired results in the experimental animals included tissue destruction via thermal vaporization or cavitation. However, while a completely non-invasive procedure would be a significant advantage, this should not come at the cost of diminished effectiveness. Access to the heart by transmission of shock waves to produce cavitation is limited to a relatively small area of the myocardium. Shock waves cannot be focused effectively through tissues of different densities, such as bone, or through air spaces (e.g., lungs or thoracic cavity). Furthermore, since the energy must pass through inhomogeneous tissues (i.e., tissues of varying density, such as bone), the ultrasonic waves may be non-uniformly diffracted, refracted and/or reflected, resulting in possible variation in the focus or other distortion of the beam which may prevent the shock waves from causing cavitation. Shock waves also must be transmitted through a liquid or solid material, and are not effectively transmitted through air spaces, such as in the lungs or thoracic cavity. Therefore, it becomes extremely difficult to treat a sufficient area of myocardium to generate the desired angiogenic result to improve clinical outcome. In TMR procedures, where many traumatic sites must be created (typically, channels on the order of 1 mm are typically made), repeatability is an important issue. Thus, while the concept of using focused ultrasound for TMR has been shown feasible in an animal laboratory, a number of issues must be addressed before ultrasound or other shock wave (cavitational) approaches can be made to be safe and effective for TMR in actual human patients. Accordingly, the need remains for relatively inexpensive surgical, minimally invasive, and non-invasive systems for performing TMR.
It is the object of this invention to provide system and method for revascularizing the heart utilizing cavitation effects to trigger and enhance angiogenesis in the myocardium.
It is further an object of this invention to induce such cavitation effects using either surgical or minimally invasive methods, either by a percutaneous, endoscopic or catheter-based device.
In an exemplary embodiment, the transcutaneous application of shockwaves is achieved using a combination lithotripsy probe/balloon system, comprising a needle and cannular balloon which can be inserted through the skin at a point between the ribs into the cavity beneath the chest wall and overlying the heart. A fluid injector is connected to the balloon, allowing it to be inflated with saline or other appropriate fluid to fill the space (for transmission of shock waves and/or to displace tissuexe2x80x94such as lung) and contact the surface of the heart. A shock-wave (acoustic) generator is used to generate shock-waves through the lithotripsy probe, through the fluid and into the myocardial tissue. The fluid provides a uniform medium for transmission of the acoustic energy, allowing precise focus and direction of the shock-wave to induce repeatable cavitation events, producing small fissures which are created by the cavitation bubbles. In this case, channels would not be xe2x80x98drilledxe2x80x99 into the heart muscle, minimizing trauma to the tissue while still creating conditions that will stimulate increased expression of angiogenic growth factors. The fluid in the balloon also stabilizes the myocardium, reducing variations which can occur do to movement of the heart as it beats, since the balloon remains in contact with the surface of the heart throughout the procedure. Visualization of the target area can be achieved using known methods including an integrated shock wave generating/transmitting endoscope or a separate optical or video-based viewing endoscope.
In another exemplary embodiment, a transcutaneous endoscopic probe has a transducer disposed at its distal end which is inserted through a small incision between the ribs, such as in CABG procedures (xe2x80x9cmidcabxe2x80x9d), so that the distal end is in contact with the heart. A small fluid-inflatable balloon may be disposed at the distal end of the endoscope, outside of the transducer, so that the balloon is positioned between the transducer and the exterior surface of the heart, or the transducer may contact the heart directly. As in the previous embodiment, the saline or other fluid in the balloon couples the shock-waves generated by a shock-wave generator to the myocardium, providing more precise focusing of the energy. In an alternate embodiment, the transducer is located in the proximal end of the endoscope, with the shock-wave conducted to the distal tip using an appropriate transmission wire.
In yet another embodiment, a laser is coupled to an optical fiber which extends coaxially through a flexible catheter or flexible/rigid endoscope. A metal cap disposed at the tip of the catheter converts the optical energy into shock-wave energy, by inducing rapid tip motion to create highly localized cavitation effects. The distal end of the catheter (or endoscope) may include a fluid-filled balloon as in the previous embodiments to couple the shock-wave directly to the myocardium.
In still another embodiment, an extracorporeal lithotripsy device is used to direct focused shock-waves toward the myocardium. A fluid-filled balloon is inserted percutaneously into the space between the inner wall of the chest and the heart to conduct the shock-wave to the heart through a uniform medium.
The system and method of the present invention can also be utilized to augment conventional cardiac surgical procedures. For example, endoscopic cavitation system can be used to induce angiogenesis to initiate improved collateral circulation as an enhancement to, and/or backup for, bypass grafts. Alternatively, a miniaturized surgical ultrasonic cavitation system can be utilized to intra-operatively produce 1 mm channels in myocardium during a CABG procedure. Testing of such a system (Verdaasdonk, Cobelensxe2x80x94University Hospital Utrecht, The Netherlands) has demonstrated that the channels produced in this fashion are essentially identical (in terms of myocardial histology) to laser-produced TMR channels.
A shock-wave generator which has been used to induce cavitation effects for treatment of human disease is the extracorporeal shock wave lithotripsy (xe2x80x9cESWLxe2x80x9d) system commonly used for breaking up kidney or ureteral stones. These systems generally utilize a spark device and reflector to create a focused shock wave that penetrates tissue and impinges at great amplitude on the stone to be fractured by a combined shock-wave and cavitation effect. Smaller, and more focused systems are currently being developed in Europe for treatment of joints. The region of shock waves could be potentially controlled by the focusing reflector, leading to a larger area of myocardium receiving shockwaves/cavitation effects more uniformly than could be achieved via a laser TMR system.
An important aspect of the invention is that the shock waves are transmitted and focused only through tissue, water, or some other solid/liquid medium. Air spaces between the skin and the myocardium will preclude delivery of shock waves. In addition, shock waves travel differently in harder tissues, such as bone, and could be defocused by traveling through the ribs. Some implementations of the present invention utilize a fluid-filled balloon, inserted via needle, between the ribs, inflated, and utilized to transmit the shock waves to the myocardium. The shock-waves are applied to the balloon using minimally-invasive or entirely non-invasive methods, relying on the density uniformity provided by the fluid to conduct the shock wave energy to a localized region within the heart tissue.
As with laser TMR systems, it may be desirable to synchronize the shock wave with the heartbeat to occur at a specified phase (e.g., T-wave) of the beat. However, with sufficiently small amplitude shock waves, such synchronization may not be required. Various embodiments of the present invention may be utilized, incorporating synchronization or not. However, unlike the laser TMR systems, the amplitude of the shock wave delivered to the myocardium can be varied over a wide range with an extracorporeal shock wave system; this may allow cumulative doses of shock waves sufficient to induce angiogenesis, while further minimizing the myocardial tissue effects of the treatment.
As it has recently been found that certain proteins may modulate the effect of vascular growth factors, e.g., the angiopoetins, ANG-1 and ANG-2, another aspect of the present invention involves the combined use of these growth factor modulators and low-amplitude shock wave treatment using a system as previously described. While delivery of genes to upregulate expression of various growth factors could be performed simultaneously with the modulators, it may be desirable to first deliver the modulators, and then at a later time to stimulate growth factors. In this case, a non-invasive (or percutaneousxe2x80x94with shock wave transmitting balloon inserted via needle) approach would be preferable to catheter-based delivery of another agent into the myocardium.